Transforming growth factor-bs (TGF-bs) are potent inhibitors of epithelial cell growth. Recently components of the TGF-b response path have been shown to be diminished or absent in a number of human malignancies, implicating loss of TGF-b function as one mechanism contributing to tumor development. However, TGF-b expression is often upregulated in advanced human cancers suggesting that the role played by the TGF-b system may be complex. We propose that TGF-bs function as conditional tumor suppressors, with suppressor activity dependent on (i) the levels of the TGF-bs and their receptors, (ii) the stage of tumorigenesis, and (iii) the nature of cooperating oncogenic events. Since the effects of TGF-b are highly context-dependent, we have chosen to study these questions in vivo in the intact organism where all the complex contextual cues such as cell-cell interaction, hormonal milieu and appropriate extracellular matrix are maintained. Our approach has been to generate genetically engineered mice in which TGF-b function is experimentally compromised in target organs. To address the role of TGF-b in breast cancer, we have generated transgenic animals overexpressing antagonists of TGF-b action in the mammary gland. To date we have used both a dominant negative mutant form of the type II TGF-b receptor (DNR), which functions as a cell-autonomous antagonist, and a soluble TGF-b antagonist consisting of the extracellular domain of the type II TGF-b receptor fused to an immunoglobulin Fc domain. Using this approach, we have shown that loss of TGF-b response causes abnormal mammary gland development and an increased susceptibility to tumorigenesis induced by chemical carcinogens. This proves that TGF-b can have tumor suppressor activity in the mammary gland. Since TGF-b is proposed to have different roles at different stages of tumorigenesis, we are currently developing regulatable transgenic models that will allow us to control the stage at which we inactivate the TGF-b system. While these systems are being developed, we are complementing the transgenic work with experiments in which we genetically modify cell lines representing different stages of the tumorigenic process, and assess tumorigenicity in a nude mouse xenograft system. Most recently, we have used a retroviral approach to introduce the DNR into premalignant prostatic epithelial cell lines in vitro. Loss of TGF-b response in these cells caused them to become tumorigenic in nude mice, indicating that TGF-b may play an important tumor suppressor role in the very early stages of prostatic tumorigenesis. Results from all these experiments should give clinically useful insights into the functions of TGF-bs during tumor initiation, promotion and progression, and illuminate how the system could be most effectively used in novel chemopreventive strategies. - Tumorigenesis, Dominant negative receptor, Transforming growth factor-beta, Breast, Mammary gland, Prostate, Retrovirus, Tumor Suppressor, Transgenic Mice